Rheumatoid arthritis (referred to as "RA" hereinafter) is a chronic multiple inflammatory disease causing arthritis as the main lesion, and the serum and synovia collected from RA patients contain a rheumatoid factor (to be referred to as "RF" hereinafter) as an autoantibody which reacts with immunoglobulin IgG. It seems that an abnormal immunity is concerned in morbidity in RA in view of the presence of RF, but the cause of this disease is still unclear. Changes in morbidity in RA are divided approximately into three stages as a matter of convenience (Zvaifler N. J., Adv. Immunol., 16, 265-336, (1973)). The first stage is an initial stage in which an unknown etiologic factor, namely an antigen, reaches joint synovial membrane to cause synovitis. In the second stage, chronic inflammation develops widely triggered by the synovitis, to cause, for example, new formation of microvessels under the surface layer of the synovial membrane, edema in tissues under the synovial membrane and proliferation, hypertrophy and multilayered growth of surface layer synovial cells. Also, infiltration of lymphoid follicle-like lymphocytes and plasma cell infiltration occur around microvessels. In the third stage, the inflamed synovial membrane is transformed into a slender villus (pannus) which penetrates into the joint cavity and subsequently proceeds to destruction of cartilage and bone, and finally acampsia. Since the destruction of cartilage and bone in the third stage entails clinically serious functional disorder and impedes the daily life of RA patients, the third stage is concerned in most important morbidity to be treated, in addition to the prevention of the initial stage synovitis. Mechanism of the cartilage destruction includes direct decomposition of proteoglycan through the joint surface by digestive enzymes such as proteases which are released into the RA synovia in a large quantity and destruction of cells and tissues at the junction of the synovial tissue with the articular cartilage by the synovial membrane pannus. Thus, decrease in the amount of proteoglycan can be found in the cartilage surface layer of RA patients. It is said that in the RA cases, the articular cartilage surface layer is coated with an immune complex containing a fibronectin-like substance, which makes pannus advanced. Especially, fibronectin is regarded as a factor positively concerned in the extension of pannus, because it is known as a mesenchymal cell extending factor and produced in the active RA synovial membrane in a markedly large quantity (Shiozawa S., Scand. J. Rheu., Suppl.74, 56-72, 1988).
As described above, the cause of RA is still unclear, and no reliable treatment of the disease has been established. Especially, there is no drug which is effective for suppressing the extension of pannus. In addition, the drugs currently used in the treatment of RA are insufficient in their effects and have a problem of causing serious side effects. In consequence, great concern has been directed toward the development of drugs which can improve the above-mentioned various symptoms of RA.
With regard to an animal model, arthritis of a rabbit induced by sensitization with heat-killed cells of an E. coli strain 0:14 is characterized in that it shows symptoms which are considerably close to those of RA (Aoki, S., et al., Arthritis and Rheumatism, 28., 522-528, 1985; Aoki, S., Chubu Rheum. Assoc., 21, 1-13, 1990). That is, this arthritis rabbit is excellent as an RA animal model because an RF-like substance as an autoantibody specific for IgG can be detected in its serum, in addition to articular pathosis such as multilayered growth of the synovial membrane surface layer cells, edema under the surface layer cells, small circle infiltration of lymphoid follicle, fibrinoid deposition, pannus formation and the like.
Similar RA-like symptoms can also be found in the case of arthritis induced by an antigen which is caused by sensitizing heat-killed cells of the E. coli strain 0:14 for several months and then directly administering the heat-killed cells into the joint cavity of the knee, in order to generate arthritis synchronously at an early stage with certainty.
The present inventors previously succeeded in synthesizing a lipid-bound glycosaminoglycan by covalently bonding glycosaminoglycan with a lipid and found that it was possessed of cell adhesion-inhibiting and metastasis-suppressing activities (JP-A-4-80201; JP-A-4-80202; JP-A-4-82836; Seikagaku, 62 (7), 880, 1990; and Seikagaku, 63 (8), 948, 1991). (The term "JP-A" as used herein means an "unexamined published Japanese patent application")
Thus, as described above, great concern has been directed toward the development of an antirheumatic drug which has excellent therapeutic effects and is free from side effects such as toxicity and the like.